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Method of disrupting heme transport in nematodes and of modelling and evaluating eukaryotic heme transport

a technology of parasitic helminths and heme transport, which is applied in the field of disrupting heme transport in parasitic helminths, and a method of modelling and evaluating eukaryotic heme transport, can solve the problems of iron deficiencies in the environment, affecting intelligence and congnition in children, and not being easily assimilated by mammals, so as to prevent helminthic infections in plants

Inactive Publication Date: 2006-09-14
UNIV OF MARYLAND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0015] It is, moreover, an object of the present invention to provide a method of treating as well as preventing against helminthic infections in plants, which entails either treating a plant or soil in which the plant is located with one or more compounds which disrupt heme transport in the helminth.

Problems solved by technology

Perinatal iron deficiency negatively impacts intelligence and congnition in children.
Yet, iron deficiencies exist as much of the iron in the environment is not easily assimilated by mammals for essential metabolic processes.
For example, iron in plants is not readily bioavailable to humans because plant-derived constitutents such as phytates interfere with its absorption across the intestine.
Although it has been postulated that heme-iron is absorbed across the intestine by an active, energy-dependent and inducible process that may require a heme transporter identification of such a heme transport system has proved to be intractable due to lack of genetic and molecular tools to directly identify the genes involved.
As observed with humans who absorb dietary heme as an iron source, some prokaryotes also utilize heme-iron living within the milieu of a eukaryotic host, where free iron is not readily available.
Helminthic infections are a serious burden to public health and global agriculture.
More than two billion people are infected by helminthiases and schistosomes, and plant-parasitic nematodes cause an estimated annual crop loss of eighty billion dollars.
However, it is unclear why these nematodes require heme to grow and whether this nutritional necessity also exists in related helminths.
Further, despite extensive current knowledge of heme biosynthesis and the intermediates of this pathway in both prokaryotes and eukaryotes, the means by which heme is processed from the point of synthesis to its insertion into hemoproteins is unknown.
However, to date, knowledge regarding eukaryotic heme transport mechanisms beyond synthesiss is unavoidable.

Method used

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  • Method of disrupting heme transport in nematodes and of modelling and evaluating eukaryotic heme transport
  • Method of disrupting heme transport in nematodes and of modelling and evaluating eukaryotic heme transport
  • Method of disrupting heme transport in nematodes and of modelling and evaluating eukaryotic heme transport

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example 1

[0082] Synchronized wild-type N2 worms (˜300 late L4 larvae), grown aseptically in CeHR growth medium, are mutagenized with 50 mM ethyl methanesulfonic acid (EMS) (Sigma) for 4 h at 20° C. EMS is used because of its proven mutagenic ability, although, based upon our positive heme-based selection, a recently described transposon-based mutagenesis may also be used. The worms are washed three times with sterile M9 buffer and allowed to recover in CeHR medium at 15° C. for 12-15 h. Worms are analyzed microscopically to ensure normal morphology, and 30 mutagenized worms (P0S) will be transferred to each of the 8 separate 175 flasks (30×8=240 P0S) and allowed to lay eggs at 20° C. The worms are carefully monitored every day to check for viability and allowed go through two generations to yield L1 larvae in the F2 progeny (about 8-9 days). This yields approximately 300,000 F2 worms in each flask (30 P0×100 F1×100 F2=300,000) with ˜25% or 75,000 worms homozygous (m / m) for a mutation. Assumi...

example 2

[0097] As shown in FIG. 12, the basis of our F2 genetic screen was to identify mutants that survive and show normal growth and reproduction under high heme, because hemin concentrations of ≧800 μM results in growth arrest and lethality of wild-type worms (See FIG. 15). Synchronized wild-type N2 worms (˜6000 late L4 larvae), grown aspetically in CeHR growth medium, were mutagenized with 50 mM ethyl methanesulfonic acid (EMS) for 4 h at 20° C. (22). The worms were then washed three times with sterile M9 buffer and allowed to recover in CeHR medium at 15° C. for 12-15 h. These P0 worms were analyzed microscopically to ensure normal morphology, and 3000 mutagenized P0 worms were transferred to 10 separate T75 flasks (300×10=3000 P0) and allowed to lay eggs at 20° C. The worms were checked for viability and allowed to go through one generation to yield gravid F1 adults that are heterozygous for a mutation. The F1 gravid hermaphrodite worms were treated with bleach (1.1% bleach / 0.55 M NaO...

example 3

[0184] Phenotypic Characterization C. elegans Mutants that are Disrupted in Heme Homeostatis.

[0185] Although the pathways for heme transport and trafficking in mammals are unknown, specific proteins and regulatory mechanisms have been described in bacteria and yeast that govern the acquisition of heme from the environment, including proteins that mediate heme insertion into cytochrome c. These studies provide evidence that cytotoxic molecule such as heme does not merely diffuse through lipid bilayers within cells, but is acviely assimilated. We, herein, provide a scheme for cellular heme homeostatis in eukaryotes whereby heme is translocated across biological membranes via specific transporters and subsequently trafficked to different cellular compartments by “heme chaperones” (FIG. 1A). Our studies with C. elegans suggest that this animal is unique because of its inability to make heme albeit requiring heme to survive. Thus, C. elegans provides an excellent eukaryotic paradigm to ...

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Abstract

A method for treating helminthic infections in a mammal or plant which entails administering one or more compounds which are metal-ligand chelate compounds containing a metal and a tetrapyrrole compound or a porphyrin compound, to mammal or plant in need thereof.

Description

FIELD OF THE INVENTION [0001] The present invention relates to a method of disrupting heme transport in parasitic helminths, and a method of modelling and evaluating eukaryotic heme transport. DESCRIPTION OF THE BACKGROUND [0002] Iron deficiency is the most common nutritional disorder. According to the World Health Organization, four out of five people in the world may be iron deficient, making nutritional iron deficiency one of the top ten risk factors in both developed and developing countries. See Micronutrient deficiencies. Battling iron deficiency anemia: The challenge 2003 http: / / www.who.int / nut / ida / htm. In developing countries, iron deficiency is multi-factorial due to dietary insufficiencies that are compounded by destruction of red cells from endemic malaria and intestinal bleeding because of parasitic hookworms. See Oppenheimer, S. J., J. Nutr. 131, 6165-6335 (2001). In the United States, iron deficiency is most prevalent among minority females and young children. Perinata...

Claims

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Application Information

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IPC IPC(8): A01K67/033
CPCA01K67/033A01K67/0333A01K2217/05A01K2217/075A01K2227/703A01K2267/0393C12N15/8509
Inventor HAMZA, IQBAL
Owner UNIV OF MARYLAND
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